Synthesis of 13C-labeled parabens from isotopically enriched phenols using the Houben–Hoesch reaction

Parabens are antimicrobial additives found in a wide array of consumer products. However, the halogenated compounds formed from parabens during wastewater disinfection are a potential environmental concern. In order to identify these transformation products and investigate their mechanism of formation, a synthetic route to ethyl parabens labeled with the stable isotope carbon-13 at specific positions within the benzene ring was developed. This efficient two-step procedure starts from commercially available ¹³C-labeled phenols and involves (1) initial acylation of the phenol via a Houben–Hoesch reaction with trichloroacetonitrile followed by (2) a modified haloform reaction of the resulting trichloromethyl ketone to afford the corresponding ¹³C-labeled ethyl parabens in 65%–80% overall yield. The scope of the modified haloform reaction was also investigated, allowing for the synthesis of other parabens derived from primary or secondary alcohols, including ¹³C- and deuterium-labeled esters. In addition, 4-hydroxybenzoic acid can be formed directly from the common trichloromethyl ketone intermediate upon treatment with lithium hydroxide. This protocol complements existing methods for preparing ¹³C-labeled paraben derivatives and offers the specific advantages of exhibiting complete regioselectivity in the Houben–Hoesch reaction (to form the para-disubstituted product) and avoiding the need for protecting groups in the modified haloform reaction that forms the paraben esters.     

Coronary Artery Disease Manifestations in HIV: What,How, and Why

Understanding why persons with human immunodeficiency virus (HIV) have accelerated atherosclerosis and its sequelae, including coronary artery disease (CAD) and myocardial infarction, is necessary to provide appropriate care to a large and aging population with HIV. In this review, we delineate the diverse pathophysiologies underlying HIV-associated CAD and discuss how these are implicated in the clinical manifestations of CAD among persons with HIV. Several factors contribute to HIV-associated CAD, with chronic inflammation and immune activation likely representing the primary drivers. Increased monocyte activation, inflammation, and hyperlipidemia present in chronic HIV infection also mirror the pathophysiology of plaque rupture. Furthermore, mechanisms central to plaque erosion, such as activation of toll-like receptor 2 and formation of neutrophil extracellular traps, are also abundant in HIV. In addition to inflammation and immune activation in general, persons with HIV have a higher prevalence than uninfected persons of traditional cardiovascular risk factors, including dyslipidemia, hypertension, insulin resistance, and tobacco use. Antiretroviral therapies, although clearly necessary for HIV treatment and survival, have had varied effects on CAD, but newer generation regimens have reduced cardiovascular toxicities. From a clinical standpoint, this mix of risk factors is implicated in earlier CAD among persons with HIV than uninfected persons; whether the distribution and underlying plaque content of CAD for persons with HIV differs considerably from uninfected persons has not been definitively studied. Furthermore, the role of cardiovascular risk estimators in HIV remains unclear, as does the role of traditional and emerging therapies; no trials of CAD therapies powered to detect clinical events have been completed among persons with HIV.     

Genomic Dissection of Travel-Associated Extended-Spectrum-Beta-Lactamase-Producing Salmonella enterica Serovar Typhi Isolates Originating from the Philippines: a One-Off Occurrence or a Threat to Effective Treatment of Typhoid Fever?

One unreported case of extended-spectrum-beta-lactamase (ESBL)-producing Salmonella enterica serovar Typhi was identified, whole-genome sequence typed, among other analyses, and compared to other available genomes of S. Typhi. The reported strain was similar to a previously published strain harboring bla_SHV-12 from the Philippines and likely part of an undetected outbreak, the first of ESBL-producing S. Typhi.     

Use of colony-stimulating factor primary prophylaxis and incidence of febrile neutropenia from 2010 to 2016: a longitudinal assessment

Background: Guidelines recommend primary prophylactic use of colony-stimulating factor (PP-CSF) when risk of febrile neutropenia (FN) – based on chemotherapy and patient risk factors – is high. Whether and how PP-CSF use may have changed over time (e.g. due to guideline revisions, increasing use of myelosuppressive regimens, controversy regarding inappropriate CSF use), and whether there has been a concomitant change in the incidence of FN, is unknown.

Methods: A retrospective cohort design and data from two US healthcare claims repositories were employed. The study population included patients who had non-metastatic cancer of the breast, colon/rectum, lung or ovaries, or non-Hodgkin’s lymphoma (NHL), and who received myelosuppressive chemotherapy regimens with an intermediate/high risk for FN. For each patient, the first cycle of the first course was characterized in terms of PP-CSF use and FN episodes. Crude incidence proportions for PP-CSF and FN during the first cycle were estimated by calendar quarter (2010–2016); multivariable logistic regression models were used to estimate quarter-specific adjusted mean probabilities of FN by PP-CSF use.

Results: The study population totaled 142,730 patients with breast cancer (61%), colorectal cancer (14%), NHL (11%), ovarian cancer (10%) or lung cancer (5%). PP-CSF use increased from 52% in 1Q2010 to 58% in 4Q2016; pegfilgrastim was the most commonly used agent (>96% across quarters). PP-CSF administration on the same day as chemotherapy ranged from 8 to 11% until 1Q2015, and increased to 64% by 4Q2016. Adjusted incidence proportions for FN in the first chemotherapy cycle ranged from 2.7% (95% CI: 2.3–3.0) to 3.7% (95% CI: 3.1–4.3) among those who did not receive PP-CSF, and was 2.6% (95% CI: 2.5–2.7) across quarters among those who received PP-CSF.

Conclusions: Although the use of PP-CSF is commonplace in current US clinical practice, underutilization in cancer patients receiving chemotherapy regimens with an intermediate/high risk for FN may still be an issue. Use of same-day PP-CSF increased markedly from the end of 2015, although this finding reflects (at least in part) increased uptake of pegfilgrastim delivered via an on-body injector as well as the recent change in clinical practice guidelines. Overall, patients receiving PP-CSF appear to have a lower risk of FN during the first cycle of chemotherapy.     

Prenatal Substance Use and Perceptions of Parent and Partner Use Using the 4P’s Plus Screener

Maternal and Child Health Journal - Background Prenatal substance use screening is recommended. The 4 P’s Plus screener includes questions on perceived problematic substance use in parents...